RESUMO
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood. METHODS: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study. RESULTS: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt. CONCLUSIONS: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
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Colangite , Varizes Esofágicas e Gástricas , Hipertensão Portal , Rim Policístico Autossômico Recessivo , Adolescente , Criança , Pré-Escolar , Colangite/etiologia , Varizes Esofágicas e Gástricas/etiologia , Humanos , Hipertensão Portal/etiologia , Lactente , Recém-Nascido , Rim/cirurgia , Masculino , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.
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Doença Enxerto-Hospedeiro , Transplante de Rim , Criança , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunização Passiva , Transplante de Rim/efeitos adversos , Esteroides , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Treatment with eculizumab in Shiga toxin-associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study. METHODS: Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme. RESULTS: Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS. CONCLUSION: The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Infecções por Escherichia coli/complicações , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Toxina Shiga/toxicidade , Escherichia coli Shiga Toxigênica/patogenicidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Infecções por Escherichia coli/induzido quimicamente , Infecções por Escherichia coli/microbiologia , Feminino , Síndrome Hemolítico-Urêmica/microbiologia , Síndrome Hemolítico-Urêmica/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disorder caused by a deficiency of the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which leads to overproduction of oxalate by the liver and results in urolithiasis, nephrocalcinosis and renal failure. The only curative treatment for PH1 is combined liver and kidney transplantation, which is limited by the lack of suitable organs, significant complications, and the life-long requirement for immunosuppressive agents to maintain organ tolerance. Hepatocyte-like cells (HLCs) generated from CRISPR/Cas9 genome-edited human-induced pluripotent stem cells would offer an attractive unlimited source of autologous gene-corrected liver cells as an alternative to orthotopic liver transplantation (OLT). Here we report the CRISPR/Cas9 nuclease-mediated gene targeting of a single-copy AGXT therapeutic minigene into the safe harbour AAVS1 locus in PH1-induced pluripotent stem cells (PH1-iPSCs) without off-target inserts. We obtained a robust expression of a codon-optimized AGT in HLCs derived from AAVS1 locus-edited PH1-iPSCs. Our study provides the proof of concept that CRISPR/Cas9-mediated integration of an AGXT minigene into the AAVS1 safe harbour locus in patient-specific iPSCs is an efficient strategy to generate functionally corrected hepatocytes, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of PH1.
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Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Terapia Genética , Hiperoxalúria Primária/genética , Hiperoxalúria Primária/terapia , Células-Tronco Pluripotentes Induzidas/patologia , Animais , Sequência de Bases , Loci Gênicos , Vetores Genéticos/metabolismo , Hepatócitos/citologia , Humanos , CamundongosRESUMO
BACKGROUND: Hemolytic uremic syndrome due to Shiga toxin-producing E. coli (STEC-HUS) is the main cause of acute kidney injury in young children. Most fully recover kidney function; however, some develop long-term sequelae. We aimed to determine whether kidney injury 1 year after HUS onset is associated with long-term kidney outcome in pediatric STEC-HUS. METHODS: A retrospective population-based study of children < 15 years with STEC-HUS between 1992 and 2012 was performed. Mixed effects logistic regression was used to investigate associations between kidney injury at 1 year and long-term kidney outcome. RESULTS: Ninety-eight STEC-HUS cases were reported. Of 96 patients who survived acute phase, 84 were evaluated at 1-year follow-up of whom 42 (44% of survivors) showed ≥ 1 signs of kidney injury. Data from 81 patients were collected after median follow-up of 8.7 (IQR 3.5-12.7) years. At last follow-up, 42 (44% of survivors) had ≥ 1 signs of kidney injury including decreased estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 (n = 30), proteinuria (n = 17), or hypertension (n = 5). Among 42 patients with kidney injuries at 1-year follow-up, only 22 (52%) still had kidney disease at last follow-up. Conversely, of 33 patients without kidney injury at 1-year and available long-term outcome data, 11 (33%) had proteinuria or decreased GFR at last follow-up. There was no statistically significant association between kidney injury at 1 year and long-term kidney outcome. CONCLUSIONS: Since kidney sequelae may appear at variable time intervals after acute HUS, all patients need lifelong follow-up to detect early signs of chronic kidney disease and propose measures to slow progression.
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Injúria Renal Aguda/epidemiologia , Diarreia/epidemiologia , Infecções por Escherichia coli/epidemiologia , Taxa de Filtração Glomerular , Síndrome Hemolítico-Urêmica/epidemiologia , Rim/fisiopatologia , Insuficiência Renal Crônica/epidemiologia , Escherichia coli Shiga Toxigênica/patogenicidade , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/terapia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diarreia/diagnóstico , Diarreia/microbiologia , Diarreia/terapia , Progressão da Doença , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/terapia , Feminino , França/epidemiologia , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/terapia , Humanos , Incidência , Lactente , Masculino , Prevalência , Prognóstico , Proteinúria/epidemiologia , Proteinúria/fisiopatologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Hemolytic uremic syndrome (HUS) has been associated with a number of infectious agents. We report here the case of an infant with severe Bordetella pertussis infection who developed HUS. CASE DIAGNOSIS/TREATMENT: A 2-month-old preterm male was admitted for severe Bordetella pertussis infection. Symptoms leading to a diagnosis of hemolytic uremic syndrome (HUS) rapidly appeared: hemolytic anemia, thrombocytopenia, and acute kidney injury. He was treated with 25 days of peritoneal dialysis and received complement-targeting therapy with eculizumab (five injections over 2 months), in addition to blood transfusions, antibiotics, and respiratory support. The outcome was favorable. The genetic workup found a complement factor H gene variant which has been associated with atypical HUS. This variant was located in the C3b-binding site and functional tests revealed that it perturbed the regulatory activity of factor H. CONCLUSION: This case suggests that pertussis is a strong trigger of HUS and that complement investigations are necessary to guide treatment and understand the pathophysiology.
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Síndrome Hemolítico-Urêmica Atípica/microbiologia , Bordetella pertussis/imunologia , Complemento C3b/metabolismo , Fator H do Complemento/genética , Coqueluche/complicações , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Sítios de Ligação/genética , Transfusão de Sangue , Bordetella pertussis/isolamento & purificação , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Complemento C3b/imunologia , Fator H do Complemento/metabolismo , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Diálise Peritoneal , Polimorfismo de Nucleotídeo Único , Coqueluche/imunologia , Coqueluche/microbiologiaRESUMO
BACKGROUND: Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results. METHODS: On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18). RESULTS: Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported. CONCLUSIONS: Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Escherichia coli Shiga Toxigênica/isolamento & purificação , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Criança , Pré-Escolar , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Complemento C5/antagonistas & inibidores , Complemento C5/imunologia , Inativadores do Complemento/farmacologia , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Seguimentos , Síndrome Hemolítico-Urêmica/complicações , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.
Assuntos
Glucocorticoides/uso terapêutico , Cadeias alfa de HLA-DQ/genética , Glicoproteínas de Membrana/genética , Síndrome Nefrótica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome Nefrótica/tratamento farmacológico , Análise de Sequência de DNA/métodos , Adulto JovemRESUMO
Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.
Assuntos
Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: An outbreak of haemolytic uraemic syndrome (HUS) due to Shiga toxin-secreting Escherichia coli (STEC) O104:H4 from contaminated fenugreek sprouts occurred in June 2011 near Bordeaux, France. In the context of this outbreak, all patients were treated with the monoclonal anti-C5 antibody, eculizumab. METHODS: The diagnosis of HUS was made based on haemolytic anaemia, low platelet count and acute kidney injury. Data were obtained from initial gastrointestinal symptoms to the end of follow-up 10 weeks after the start of eculizumab. RESULTS: Among 24 cases of STEC gastroenteritis, HUS developed in nine patients (eight adults and one child), 6 (median; range 3-12) days after digestive symptoms begun. The median (range) highest or lowest biological values were platelet count 26 (range 14-93) G/L; haemoglobin 6.6 (range 5-10.7) g/dL; LDH 1520 (range 510-2568) IU/L; creatinine 152 (range 48-797) µmol/L. All patients had extra-renal complications (liver 9, pancreas 5, brain 3 and heart 3). Two patients were dialysed, and one was ventilated. After failure of plasma exchange to increase platelets in the first three patients, eculizumab was administered in all nine patients, 0-4 days after HUS diagnosis (median 1 day). One patient with very severe neurological HUS received immunoadsorption. Outcome was favourable in all patients, with rapid normalization of haemoglobin, platelets, LDH levels, renal function and neurological improvement. There were no deaths and no serious adverse events related to eculizumab. CONCLUSIONS: Early treatment of O104:H4 STEC-HUS by eculizumab was associated with a rapid and efficient recovery. Controlled prospective evaluation of eculizumab in STEC-HUS is warranted.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Surtos de Doenças , Infecções por Escherichia coli/tratamento farmacológico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Escherichia coli Shiga Toxigênica , Adulto , Pré-Escolar , Diarreia/tratamento farmacológico , Diarreia/epidemiologia , Diarreia/microbiologia , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/epidemiologia , Feminino , França , Síndrome Hemolítico-Urêmica/epidemiologia , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Introduction: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling.
RESUMO
BACKGROUND: About half of children with steroid-sensitive idiopathic nephrotic syndrome (INS) will develop steroid dependency or a frequently relapsing course requiring steroid-sparing agents (SSA). Because of the adverse effects of prolonged steroid treatment, the early identification of children at high risk of requiring SSA may be a useful diagnostic tool to tailor the therapeutic strategy. The aim of this study was to identify predictors of the need for SSA and derive a predictive model. METHODS: This was a retrospective hospital-based cohort study which included all children with steroid-responsive INS followed for at least 4.5 months. Cox regression modeling and decision curve analysis were performed. RESULTS: A total of 120 children (81 boys) with INS were included and followed up for a median time of 6.7 (range 0.4-24.1) years. Median age at diagnosis was 3.4 years. Seventy-two (60 %) children required a SSA after a median time of 10 months following initial diagnosis. Male children, age at disease onset, methylprednisolone pulse use, and time to achieve first remission were significantly associated with the outcome. Time to achieve remission only remained significant after adjustment: hazard ratio (HR) =1.9 [95 % confidence interval (CI) 1.5-2.5] if considered as a continuous variable, and HR=4.1 (95 % CI 1.9-8.6) when dichotomized using the 9-day threshold. The area under the receiver operating curve of the related predictive model was 0.81 (95 % CI 0.74-0.89), and the decision curve analysis demonstrated that this model performed better than any other strategy. CONCLUSIONS: Time to first remission is a strong predictor of the need for SSA in pediatric INS. Further prospective and impact studies are warranted to confirm the accuracy and benefit of our prediction model.
Assuntos
Substituição de Medicamentos , Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Esteroides/uso terapêutico , Adolescente , Área Sob a Curva , Criança , Pré-Escolar , Técnicas de Apoio para a Decisão , Intervalo Livre de Doença , Feminino , Hospitais Universitários , Humanos , Imunossupressores/efeitos adversos , Lactente , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Modelos de Riscos Proporcionais , Curva ROC , Recidiva , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Esteroides/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Mycoplasma pneumoniae can cause various extrapulmonary manifestations but, to our knowledge, no case of Mycoplasma pneumoniae associated with hemolytic uremic syndrome (HUS) has been reported. CASE-DIAGNOSIS/TREATMENT: We describe a 1-year-old boy with M. pneumoniae respiratory tract infection and associated microangiopathic hemolytic anemia, slightly decreased platelet count and mild renal impairment, suggesting a diagnosis of HUS. Assuming M. pneumoniae infection was the cause of HUS in this case, the different possible mechanisms, including an atypical HUS due to preexisting complement dysregulation, an alternative complement pathway activation induced by M. pneumoniae infection at the acute phase, an autoimmune disorder, and a direct role of the bacteria in inducing endothelial injury, are discussed. The signs of HUS resolved with treatment of the M. pneumoniae infection. CONCLUSIONS: Hemolytic uremic syndrome may be an unusual complication of M. pneumoniae infection.
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Síndrome Hemolítico-Urêmica/microbiologia , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/microbiologia , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Síndrome Hemolítico-Urêmica/imunologia , Humanos , Lactente , Masculino , Mycoplasma pneumoniae/imunologia , Pneumonia por Mycoplasma/sangue , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Rituximab (RTX) has recently showed promising results in the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS). METHODS: This was a retrospective multicenter study of 18 children treated with RTX for SDNS, with a mean follow-up of 3.2 years. RTX was introduced because of side effects or relapses during therapy with immunosuppressive agents. The children received one to four infusions of RTX during the first course of treatment, and subsequent infusions were given due to CD19-cell recovery (CD19 >1 %; 54 % of children) or relapse (41 %), as well as systematically (5 %). RESULTS: Treatment with RTX maintained sustained remission without relapse in 22 % of patients and increased the duration of remission in all other patients. The time between two successive relapses was 9 months in the absence of re-treatment and 24.5 months when infusions were performed at the time of CD19-cell recovery. At the last follow-up, 44.5 % of patients were free of oral drug therapy. Of those still receiving oral drugs, all doses had been decreased. No serious adverse events occurred. CONCLUSION: The results of this retrospective study confirm the efficacy and very good safety of RTX in the treatment of SDNS. The optimal therapeutic protocol seems to be a repeated single infusion at the time of CD19-cell recovery.
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Anticorpos Monoclonais Murinos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Anticorpos Monoclonais Murinos/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Rituximab , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Leptospirosis is an anthropozoonosis with polymorphic clinical symptoms and a high variability of severity, ranging from flu-like syndrome to severe acute kidney injury. This disease is highly incident in tropical regions but there is a trend towards increasing incidence in metropolitan France and in Reunion Island. The objective of this study was to describe the epidemiological, clinical, laboratory and therapeutic characteristics of the pediatric leptospirosis in metropolitan France and in Reunion Island. PATIENTS AND METHODS: We performed a retrospective analysis of leptospirosis cases hospitalized in University hospitals where members of the Paediatric Nephrology Society work in France between January 2008 and December 2020, 6 centers reported leptospirosis cases, one center had one patient in consultation but lack of available data and 10 centers did not find any case. RESULTS: A total of 21 cases were reported (mean age 13.4±3.4years), mostly boys (ratio 6:1). Out of 21 patients, 95% had fever, 71% were presenting with myalgia, 81% with thrombocytopenia, and 76% with gastrointestinal symptoms. Regarding kidney impairment, 18 patients (86%) had acute kidney injury, including 4 (19%) with oligoanuria, but none of them required acute dialysis. About 30% of patients had biological signs of tubulopathy including hypophosphatemia, hypokalemia, or tubular proteinuria. No death due to the disease occurred. The therapeutic management followed the current guidelines with the use of antibiotic therapy by amoxicillin or 3rd generation cephalosporins with symptomatic treatment. When there was biological control after exit, creatinine decreased. DISCUSSION: In this multicenter retrospective study, we report 21 children with leptospirosis with a significant proportion of acute kidney injury, the outcome was favorable. Children do not seem to be at high risk of chronic kidney disease progression but nephrology follow-up has not been systematically carried out. Compared to studies performed in adults, the prognosis was better and hepatic impairment was rare. Compared to other pediatric studies, conjunctivitis was not a common symptom but kidney injury and survival appeared to be similar. Children were presenting with anicteric renal presentation. The casebook wasn't exhaustive and didn't include the other overseas territories, which account for the highest proportion of leptospirosis infection. CONCLUSION: Leptospirosis is an infection which may lead to multivisceral failure with kidney involvement conditioning the outcome. Despite a better prognosis in children, it remains important to quickly diagnose this infection in order to start appropriate antibiotic therapy and perform a kidney function monitoring.
Assuntos
Injúria Renal Aguda , Leptospirose , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Adolescente , Adulto , Antibacterianos/uso terapêutico , Criança , Feminino , Humanos , Rim , Leptospirose/complicações , Leptospirose/diagnóstico , Leptospirose/tratamento farmacológico , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: It has been demonstrated that alkylating agents such as cyclophosphamide (CYP) are effective in reducing the risk of relapse in frequently relapsing (FRNS) and steroid-dependent nephrotic syndrome (SDNS). Little is known about prognostic factors in SDNS and FRNS treated by CYP. The objectives of this study are to determine long-term outcomes and factors associated with sustained remission in these patients. METHODS: We retrospectively studied the data from 143 children (104 boys) with SDNS and FRNS treated with CYP in six centres over 15 years. Relapse-free survival was estimated by Kaplan-Meier method. The determinants of long-term remission were assessed by univariate and multivariate analyses using Cox proportional hazard models. RESULTS: Median age at diagnosis was 3.7 years (interquartile range: IQR 2.3-5.9), and median follow-up was 7.8 years (IQR 4.0-11.8). CYP treatment was introduced after a median time of 1.7 years (IQR 0.7-5.9) after diagnosis. Patients received a median cumulative dose of 168 mg/kg (IQR 157-197) body weight. Relapse-free survival was 65%, 44%, 27% and 13% after 6 months, 1 year, 2 years and 5 years, respectively. In multivariate analysis, sustained remission >2 years was associated with age at treatment >5 years (P = 0.02) and cumulative dose of CYP >170 mg/kg (P = 0.02). Frequently relapsing versus steroid-dependent status and female gender were predictors of borderline significance. Height and body mass index standard deviation score were significantly influenced by CYP treatment. CONCLUSION: In our study, long-term efficacy of cyclophosphamide in steroid-responsive nephrotic syndrome is disappointing. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents.
Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Corticosteroides/uso terapêutico , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Nefrótica/patologia , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Tempo , Fatores de Tempo , Resultado do TratamentoRESUMO
Thrombotic microangiopathies comprise different entities, including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and several other conditions. TTP is characterized by hemolytic anemia, thrombocytopenia, and multiorgan failure. TTP is the result of severe von Willebrand factor multimer cleaving protease (ADAMTS13) deficiency that is either inherited or the result of acquired autoantibodies. We report a critically ill 2-year-old girl with invasive pneumococcal disease associated HUS (p-HUS) whose condition was complicated by severe ADAMTS13 deficiency, without detectable inhibitor, in a context of multiple organ failure. The patient recovered with supportive treatment, and ADAMTS13 activity normalized without plasmatherapy. Severe ADAMTS13 deficiency appears to be a manifestation of transient endothelial cell injury in the context of severe sepsis, including invasive p-HUS. The choice of appropriate therapy should not be based on this finding.
Assuntos
Proteínas ADAM/deficiência , Síndrome Hemolítico-Urêmica/fisiopatologia , Pneumonia Pneumocócica/complicações , Proteína ADAMTS13 , Pré-Escolar , Feminino , Síndrome Hemolítico-Urêmica/metabolismo , Síndrome Hemolítico-Urêmica/microbiologia , HumanosRESUMO
OBJECTIVE: To report the case of a child with severe autoimmune thrombotic thrombocytopenic purpura (TTP) resistant to plasma exchange and steroids who was successfully treated with rituximab. DESIGN: Case report and review of the literature on pediatric acquired TTP. The report was approved by an independent local ethics committee. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENT: A 10-yr-old boy was referred to the emergency unit with fever, vomiting, confusion, hemolytic anemia, thrombocytopenia, and mild acute renal failure. An atypical hemolytic uremic syndrome was suspected, and plasma exchange was started urgently. The patient was refractory to plasma therapy and presented critical complications. After a diagnosis of acquired TTP attributable to anti-ADAMTS13 autoantibodies had been made, he was treated with rituximab, which resulted in a stable clinical remission. INTERVENTIONS: Rituximab therapy. MEASUREMENTS AND MAIN RESULTS: Clinical remission. CONCLUSIONS: TTP is a rare but life-threatening condition in children that is characterized by hemolytic anemia, thrombocytopenia, and signs of ischemic organ dysfunction. If renal involvement is present, TTP may be misdiagnosed as hemolytic uremic syndrome, but reliable screening for ADAMTS13 activity and anti-ADAMTS autoantibodies allow us to distinguish the two entities and provide adequate therapy.
Assuntos
Proteínas ADAM/deficiência , Anticorpos Monoclonais Murinos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Proteínas ADAM/imunologia , Proteína ADAMTS13 , Criança , Humanos , Unidades de Terapia Intensiva Pediátrica , Masculino , Avaliação de Resultados em Cuidados de Saúde , Púrpura Trombocitopênica Trombótica/fisiopatologia , RituximabRESUMO
The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
Assuntos
Desempenho Acadêmico/estatística & dados numéricos , Fator 1-beta Nuclear de Hepatócito/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Criança , Feminino , Deleção de Genes , Humanos , Rim/anormalidades , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , SíndromeRESUMO
Primary hyperoxaluria type 1 results from alanine:glyoxylate aminotransferase deficiency. Due to genotype/phenotype heterogeneity in this autosomal recessive disorder, the renal outcome is difficult to predict in these patients and the long-term impact of conservative management in children is unknown. We report here a multicenter retrospective study on the renal outcome in 27 affected children whose biological diagnosis was based on either decreased enzyme activity or identification of mutations in the patient or his siblings. The median age at first symptoms was 2.4 years while that at initiation of conservative treatment was 4.1 years; 6 children were diagnosed upon family screening. The median follow-up was 8.7 years. At diagnosis, 15 patients had an estimated glomerular filtration rate (eGFR) below 90, and 7 children already had stage 2-3 chronic kidney disease. The median baseline eGFR was 74, which rose to 114 with management in the 22 patients who did not require renal replacement therapy. Overall, 20 patients had a stable eGFR, however, 7 exhibited a decline in eGFR of over 20 during the study period. In a Cox regression model, the only variable significantly associated with deterioration of renal function was therapeutic delay with a relative risk of 1.7 per year. Our study strongly suggests that early and aggressive conservative management may preserve renal function of compliant children with this disorder, thereby avoiding dialysis and postponing transplantation.